Role In Heart Failure With Preserved Ejection Fraction Research Articles

Interplay of the heart, spleen, and bone marrow in heart failure: the role of splenic extramedullary hematopoiesis.

Improvements in therapies for heart failure with preserved ejection fraction (HFpEF) are crucial for improving patient outcomes and quality of life. Although HFpEF is the predominant heart failure type among older individuals, its prognosis is often poor owing to the lack of effective therapies. The roles of the spleen and bone marrow are often overlooked in the context of HFpEF. Recent studies suggest that the spleen and bone marrow could play key roles in HFpEF, especially in relation to inflammation and immune responses. The bone marrow can increase production of certain immune cells that can migrate to the heart and contribute to disease. The spleen can contribute to immune responses that either protect or exacerbate heart failure. Extramedullary hematopoiesis in the spleen could play a crucial role in HFpEF. Increased metabolic activity in the spleen, immune cell production and mobilization to the heart, and concomitant cytokine production may occur in heart failure. This leads to systemic chronic inflammation, along with an imbalance of immune cells (macrophages) in the heart, resulting in chronic inflammation and progressive fibrosis, potentially leading to decreased cardiac function. The bone marrow and spleen are involved in altered iron metabolism and anemia, which also contribute to HFpEF. This review presents the concept of an interplay between the heart, spleen, and bone marrow in the setting of HFpEF, with a particular focus on extramedullary hematopoiesis in the spleen. The aim of this review is to discern whether the spleen can serve as a new therapeutic target for HFpEF.

Transcriptional regulation of macrophage inflammation in the heart failure with preserved ejection fraction

Abstract Funding Acknowledgements None. Introduction Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with no effective treatment available. Pro-inflammatory cardiac macrophages are emerging as key determinants of adverse left ventricular remodeling; however, their role in HFpEF remains poorly understood. Mechanistically, the recruitment and activation of macrophages represent a key event in maladaptive myocardial remodeling in HFpEF patients. Evidence suggests that remodeling processes in HFpEF hearts are orchestrated and amplified by cardiac macrophages which regulate cardiomyocyte function, endothelial cell activation and fibroblast differentiation. Here we sought to determine the role of macrophage inflammation in experimental and human HFpEF. Methods Experiments were performed in rat cardiomyocytes (H9c2), human endothelial cells (HAECS), transgenic mice, and left ventricular (LV) myocardial samples from patients with HFpEF. H9c2 and HAECS treated with pro-inflammatory macrophage-like cells (RAW 264.7) conditional media in the presence or knockdown of a top-ranking activator of M1 type macrophages such as nuclear receptor corepressor 1 (NCOR1), were used to elucidate better the involvement of this gene in transcriptional regulation in vitro. The cardiac function of myeloid cell-specific NCOR1 knockout HFpEF mice undergoing a high-fat diet and L-NAME was investigated. LV myocardial samples were used to evaluate the pro-inflammatory activity of macrophages in human HFpEF tissues. Results Human and murine LV specimens showed upregulation of vascular adhesion molecules (ICAM1, ICAM2, E-selectin), recruitment of M1 macrophages to the myocardium, and decreased M2 macrophages. Notably, NCOR1 deletion in macrophages protected against diastolic dysfunction, exercise intolerance, and myocardial inflammation (TNF-a, IL6, IL-1b). Mechanistically, induction of metabolic stress by palmitic acid induced macrophage polarization, upregulation of NCOR1 and inflammatory genes in RAW cells. By contrast, Finally, NCOR1 depletion prevented pro-inflammatory transcriptional programs and secretion of TNF-a, IL6 and IL-1b in the macrophage secretome. Conclusion Targeting macrophage NCOR1 could represent a promising approach to blunt myocardial inflammation in HFpEF.

Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice

Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6’s role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018’s effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.

Heart failure with preserved ejection fraction: the role of microvascular dysfunction

Aim. To evaluate the relationship between coronary microvascular dysfunction (CMD), biomarkers of cardiac fibrosis and cardiac remodeling (soluble ST2 (sST2), fibroblast growth factor-23 (FGF-23), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and NT-proBNP), parameters of diastolic dysfunction (DD), and the presence of heart failure with preserved ejection fraction (HFpEF) in symptomatic patients.Materials and methods. Study participants were 59 patients with non-obstructive coronary artery disease (CAD) and preserved left ventricular ejection fraction (LVEF) of 62 (56; 67) %. Non-obstructive CAD was verified by coronary computed tomography angiography. Stress-and rest-myocardial blood flow (MBF) and coronary flow reserve (CFR) parameters were evaluated by CZT SPECT. Serum levels of cardiac biomarkers were measured by the enzyme immunoassay. Two-dimensional transthoracic echocardiography was used to assess DD parameters.Results. Decreased CFR was defined as CFR ≤ 2. Therefore, CMD was defined as the presence of decreased CFR in the absence of flow-limiting CAD. Distribution of patients was performed by CFR values: group 1 included patients with preserved CFR (>2, n = 35), and group 2 encompassed patients with decreased CFR (≤2, n = 24). In 87.5% of cases, patients with CMD were diagnosed with HFpEF, whereas in patients with preserved CFR, heart failure was diagnosed only in 51.4% of cases (p < 0.0001). CFR values were correlated with the left atrial volume (r = –0.527; p = 0.001), E / A ratio (r = –0.321, p = 0.012), and E / e’ (r = –0.307; p = 0.021). Following the ROC analysis, the levels of sST2 ≥ 31.304 ng / ml (AUС = 0.730; р = 0.004) and NT-proBNP ≥ 0.034 pg / ml (AUС = 0.815; р = 0.034) were identified as cut-off values for the presence of CMD in patients with non-obstructive CAD.Conclusion. The obtained data suggest that CMD may play an essential role in HFpEF. The values of CFR were correlated with DD parameters, and decreased CFR was associated with overexpression of biomarkers of cardiac fibrosis and cardiac remodeling. Serum levels of sST2 and NT-proBNP were identified as cut-off values for the presence of CMD in patients with non-obstructive CAD.

S-12-4: CITE-SEQ IDENTIFIES TREM2-DEPENDENT GENE PROGRAM DRIVING CARDIAC REMODELING IN A HYPERTENSIVE MODEL OF HEART FAILURE WITH PRESERVED EJECTION FRACTION

Objective: The deoxycorticosterone acetate (DOCA)-salt model of hypertension has been used to study diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) in rats. Our goal was to validate DOCA-salt as a mouse model of HFpEF and to identify immune mediators of cardiac remodeling using CITE-Seq, a novel single cell technique that provides surface marker and transcriptomic data. Methods: DOCA-salt mice underwent uninephrectomy, DOCA pellet implantation, and 1% NaCl supplementation of the drinking water for three weeks. Control mice underwent a sham procedure and received normal water. Echocardiography and invasive hemodynamics were performed to examine cardiac function, and urine was collected to examine renal function. CITE-seq was performed on sorted leukocytes from four sham and DOCA-salt left ventricles. To test whether Trem2 has a causal role in HFpEF, wild type and Trem2 deficient animals were subjected to DOCA-salt. To evaluate translational potential, soluble Trem2 was measured in plasma of patients with HFpEF and healthy controls. Results: Compared to control mice, DOCA-salt mice exhibit significantly increased systolic blood pressure, albuminuria, and cardiac hypertrophy. On echocardiography, DOCA-salt mice exhibited a preserved ejection fraction. Invasive hemodynamic studies revealed an increased tau constant (5.70 ± .24, 8.22 ± .45; n = 8,5) in DOCA-salt mice, indicating diastolic dysfunction. CITE-seq revealed major transcriptional changes in cardiac macrophages between groups with upregulation of genes known to be involved in HFpEF and cardiac remodeling, such as galectin-3 (Lgals3) and osteopontin (Spp1), as well as novel genes including Trem2. Using an independent cohort of Sham and DOCA-salt treated mice, we validated a two-fold increase in Trem2 gene expression in left ventricles by qRT-PCR and a significant increase in Trem2 mRNA in Cd68+ macrophages by RNAscope. After DOCA-salt treatment, Trem2-deficient mice displayed increased heart weight to tibia length ratios (9.39 ± 0.20, 11.21 ± 0.80; n = 6–7) and albumin to creatinine ratios (5.5 ± 1.2, 14.2 ± 2.9; n = 6–7) compared to wild-type controls. No difference in albuminuria was observed at baseline (0.36 ± 0.05, 0.46 ± 0.10; n = 10). Bone marrow-derived macrophages (BMDMs) from Trem2 deficient mice expressed significantly less Lgals3 and Spp1 compared to wild type BMDMs suggesting that Trem2 signaling is upstream of galectin 3 and osteopontin in HFpEF. Plasma levels of soluble Trem2 were elevated in patients with HFpEF compared to healthy controls (51 ± 9.5; 22.4 ± 2.4 ng/mL; n = 9,12). Conclusions: The DOCA-salt mouse model induces key features of human HFpEF and identifies a Trem2-dependent gene program involved in cardiac remodeling. Loss of Trem2 resulted in increased cardiac hypertrophy and renal damage in the DOCA-salt model of HFpEF.

Abstract P3015: Cite-seq Identifies A Novel Role For Macrophage Trem2 In A Murine Model Of Hfpef

Deoxycorticosterone acetate (DOCA)-salt is a common model of hypertension and has been used to study heart failure with preserved ejection fraction (HFpEF) in rats. Our goal was to validate DOCA-salt as a mouse model of HFpEF and to identify immune mediators of cardiac remodeling using unbiased methods. DOCA-salt mice underwent uninephrectomy, implantation of a DOCA pellet, and supplementation of the drinking water with 1%NaCl for three weeks. Control mice underwent a sham procedure and received normal water. Compared to control mice, DOCA-salt mice exhibited increased systolic blood pressure, cardiac hypertrophy, and decreased time to exhaustion upon treadmill exercise testing. In addition, DOCA-salt mice exhibited albuminuria, indicative of renal glomerular injury. On echocardiography, DOCA-salt mice exhibited a preserved ejection fraction. Invasive hemodynamic studies revealed an increased tau constant (5.70±.24, 8.22±.45; n=8,5) in DOCA-salt mice, consistent with diastolic dysfunction. CITE-seq, a novel technique to obtain transcriptomic and surface marker expression on single cells, was performed on a total of 4,359 and 7,600 sorted leukocytes from four sham and four DOCA-salt left ventricles, respectively. Differential gene expression analysis revealed major transcriptional changes in cardiac macrophages between groups and identified Trem2 as being upregulated in cardiac macrophages. We validated a two-fold increase in Trem2 gene expression in left ventricles of DOCA-salt mice and observed a two-fold increase in cardiac Trem2+Mac2+ cells in DOCA-salt by immunofluorescence. To test whether Trem2 has a causal role in HFpEF, wild type and Trem2 deficient animals were subjected to DOCA-salt. After DOCA-salt, Trem2-deficient mice displayed significantly increased heart weight to tibia length ratios (9.39±0.20, 11.21±0.80; n=6-7) and albumin to creatinine ratios (5.5±1.2, 14.2±2.9; n=6-7) compared to wild-type controls. No difference in albuminuria was observed at baseline (0.36±0.05, 0.46±0.10; n=10). In conclusion, the DOCA-salt mouse model induces key features of HFpEF and identifies Trem2 as a potential novel modulator of cardiac remodeling and renal injury.

Sex differences in heart mitochondria regulate diastolic dysfunction

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a “two-hit” mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.

Plasma metabolomics identify hydroxyproline as a potential player in the pathophysiogy of HFpEF

A better understanding of metabolic modifications occurring in heart failure with preserved ejection fraction (HFpEF) could elucidate pathophysiological pathways and reveal new biomarkers and therapeutic targets. To compare metabolic profiles of HFpEF patients with healthy controls. Plasma concentrations of 21 amino acids and 12 organic acids were assessed using gas chromatograph-mass spectrometry in 70 HFpEF patients (75 ± 7.2 years old, 57% women) and 44 “old” controls (65 ± 9.8 years old, 50% women). After adjustment for age, sex and batch effects in a linear regression model, hydroxyproline ( P = 8.19 × 10 −5 ) and cysteine ( P = 1.04 × 10 −6 ) were significantly upregulated in HFpEF compared to controls ( Fig. 1 A). In patients, hydroxyproline levels were correlated to BMI ( r = 0.29, P = 0.015), renal function ( r = −0.26, P = 0.028), septal E/e′ ( r = 0.29, P = 0.018), pulmonary pressures eSPAP ( r = 0.29, P = 0.015) and myocardial fibrosis measured by CMR extracellular volume (ECV) ( r = 0.28, P = 0.031, Fig. 1 B), but not with age, indexed LA volumes nor NTproBNP levels. In multivariate linear regression, hydroxyproline was independently associated with BMI and ECV. We did not find any significant correlation between cysteine and clinical characteristics (age, BMI, diabetes, renal function, LA volumes, E/e′ ratio, ECV or NTproBNP) ( Table 1 ). Hydroxyproline, formed by hydroxylation of proline by prolyl hydroxylase, is a key player in the synthesis and stability of collagen and may as such contribute to the myocardial structural changes in HFpEF. Hydroxyproline's specific role in HFpEF and diastolic dysfunction is intriguing, and may be relevant both as a biomarker and drug target.

The prognostic impact of mechanical atrial dysfunction and atrial fibrillation in heart failure with preserved ejection fraction.

AimsThis study assessed the prognostic implications of mechanical atrial dysfunction in heart failure with preserved ejection fraction (HFpEF) patients with different stages of atrial fibrillation (AF) in detail.Methods and resultsHFpEF patients (n = 258) systemically underwent an extensive clinical characterization, including 24-h Holter monitoring and speckle-tracking echocardiography. Patients were categorized according to rhythm and stages of AF: 112 with no history of AF (no AF), 56 with paroxysmal AF (PAF), and 90 with sustained (persistent/permanent) AF (SAF). A progressive decrease in mechanical atrial function was seen: left atrial reservoir strain (LASr) 30.5 ± 10.5% (no AF), 22.3 ± 10.5% (PAF), and 13.9 ± 7.8% (SAF), P < 0.001. Independent predictors for lower LASr values were AF, absence of chronic obstructive pulmonary disease, higher N-terminal-pro hormone B-type natriuretic peptide, left atrial volume index, and relative wall thickness, lower left ventricular global longitudinal strain, and echocardiographic signs of elevated left ventricular filling pressure. LASr was an independent predictor of adverse outcome (hazard ratio per 1% decrease =1.049, 95% confidence interval 1.014–1.085, P = 0.006), whereas AF was not when the multivariable model included LASr. Moreover, LASr mediated the adverse outcome associated with AF in HFpEF (P = 0.008).ConclusionMechanical atrial dysfunction has a possible greater prognostic role in HFpEF compared to AF status alone. Mechanical atrial dysfunction is a predictor of adverse outcome independently of AF presence or stage, and may be an underlying mechanism (mediator) for the worse outcome associated with AF in HFpEF. This may suggest mechanical atrial dysfunction plays a crucial role in disease progression in HFpEF patients with AF, and possibly also in HFpEF patients without AF.

EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex disease which accounts for more than half of all HF hospital admissions with high prevalence and lack of effective evidence-based management. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new antidiabetic drug that recently gained a new role in the management of heart failure with reduced ejection fraction but its role in HFpEF had yet to be studied.Study and results: EMPEROR-Preserved trial set out to evaluate the effects of SGLT2 inhibition with empagliflozin on major heart failure outcomes in patients with HFpEF. The patients were randomized in a 1:1 fashion into two groups; to receive either empagliflozin 10 mg per day (n = 2, 997) or placebo (n = 2, 991) in addition to usual therapy. Empagliflozin led to a 21% risk reduction of the composite of cardiovascular death or hospitalization for heart failure, which was mainly related to a 29% lower risk of hospitalization for heart failure rather than effect on cardiovascular death empagliflozin. The effects SGLT2 inhibitors were consistent in all patients.What we have learnt: The EMPEROR-Preserved trial is the first randomized controlled trial testing the efficacy and safety of SGLT2 inhibitor (empagliflozin) in patients with HFpEF. The trial proves that SGLT2 inhibitors (empagliflozin) can significantly reduce HF hospitalization with neutral effect on cardiovascular (CV) death.

Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure.

Ageing is a major risk factor for the development of cardiovascular disease (CVD) and cancer. Whilst the cumulative effect of exposure to conventional cardiovascular risk factors is important, recent evidence highlights clonal haematopoiesis of indeterminant potential (CHIP) as a further key risk factor. CHIP reflects the accumulation of somatic, potentially pro-leukaemic gene mutations within haematopoietic stem cells over time. The most common mutations associated with CHIP and CVD occur in genes that also play central roles in the regulation of inflammation. While CHIP carriers have a low risk of haematological malignant transformation (<1% per year), their relative risk of mortality is increased by 40% and this reflects an excess of cardiovascular events. Evidence linking CHIP, inflammation and atherosclerotic disease has recently become better defined. However, there is a paucity of information about the role of CHIP in the development and progression of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). While systemic inflammation plays a role in the pathophysiology of both heart failure with reduced and preserved ejection fraction (EF), it may be of greater relevance in the pathophysiology of HFpEF, which is also strongly associated with ageing. This review describes CHIP and its pathogenetic links with ageing, inflammation and CVD, while providing insight into its putative role in HFpEF.

Skeletal muscle (dys)function in heart failure with preserved ejection fraction.

Skeletal muscle dysfunction contributes to exercise intolerance, which manifests as dyspnea and fatiguability in patients with heart failure with preserved ejection fraction (HFpEF). This review aims to summarize the current understanding of skeletal muscle dysfunction in HFpEF. Animal and human studies in HFpEF provide insights into the pathophysiological alterations in skeletal muscle structure and function with the identification of several molecular mechanisms. Exercise training and novel pharmacological therapies that target skeletal muscle are proposed as therapeutic interventions to treat HFpEF. There is evidence that skeletal muscle dysfunction plays a pathophysiological role in HFpEF. However, precise mechanistic insights are needed to understand the contribution of skeletal muscle dysfunction in HFpEF.

Sex differences in heart failure

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

Natriuretic Peptides in Heart Failure with Preserved Left Ventricular Ejection Fraction: From Molecular Evidences to Clinical Implications

The incidence of heart failure with preserved ejection fraction (HFpEF) is increasing and its challenging diagnosis and management combines clinical, imagistic and biological data. Natriuretic peptides (NPs) are hormones secreted in response to myocardial stretch that, by increasing cyclic guanosine monophosphate (cGMP), counteract myocardial fibrosis and hypertrophy, increase natriuresis and determine vasodilatation. While their role in HFpEF is controversial, most authors focused on b-type natriuretic peptides (BNPs) and agreed that patients may show lower levels. In this setting, newer molecules with an increased specificity, such as middle-region pro-atrial natriuretic peptide (MR-proANP), emerged as promising markers. Augmenting NP levels, either by NP analogs or breakdown inhibition, could offer a new therapeutic target in HFpEF (already approved in their reduced EF counterparts) by increasing the deficient cGMP levels found in patients. Importantly, these peptides also retain their prognostic value. This narrative review focuses on NPs’ physiology, diagnosis, therapeutic and prognostic implication in HFpEF.

Iron deficiency in heart failure with preserved ejection fraction: a systematic review and meta-analysis

ObjectiveIron deficiency (ID) has an established impact on outcomes in patients with heart failure with reduced ejection fraction; however, there is a lack of conclusive evidence in patients with heart...

Evaluation of efficacy of metoprolol in patients having heart failure with preserved ejection fraction: A randomized, double-blind, placebo-controlled pilot trial.

Background:There is a lack of evidence-based therapies for the treatment of heart failure (HF) with preserved ejection fraction (HFpEF). Beta blockers may provide some benefit in HFpEF due to their proven role in HF with reduced ejection fraction.Aim:The main objective of the present study was to evaluate the efficacy of controlled-release metoprolol (metoprolol succinate) in HFpEF.Materials and Methods:This was an investigator-initiated, randomized, double-blind, placebo-controlled, 14-week pilot study with metoprolol succinate as a study drug. Dose titration protocol was used with optional upward titration of doses ranging from 25 to 100 mg. The end points included clinical, echocardiographic, biochemical (N-terminal pro-B-type natriuretic peptide and serum carboxy-terminal propeptide of procollagen type I), and quality of life (QoL) (SF-36) parameters.Results:Twenty patients were enrolled in each of the treatment arms. An improvement in New York Heart Association class and exercise capacity was seen in both treatment arms. The mean change in various echocardiographic and biochemical parameters between the two groups was statistically insignificant. A significant improvement in some QoL parameters was observed in both the groups. No serious adverse events were seen.Conclusion:Hence, this pilot study showed that metoprolol succinate possibly has some beneficial role in HFpEF as reflected by improvement in some parameters. The findings highlight the need of a larger study with longer follow-up to provide a definitive answer.

Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.

BackgroundVarious pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF).Methods and ResultsThis study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF.ConclusionsInflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.